rs1003307358

Variant names:

• chr14-36519521-T-C
• rs1003307358
• ENST00000498187.6:c.-164A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_003317.4(NKX2-1):​c.-164A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000286 in 1,536,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: NKX2-1 NM_003317.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.71
• Publications: 0 publications found

Genes affected

NKX2-1 (HGNC:11825): (NK2 homeobox 1) This gene encodes a protein initially identified as a thyroid-specific transcription factor. The encoded protein binds to the thyroglobulin promoter and regulates the expression of thyroid-specific genes but has also been shown to regulate the expression of genes involved in morphogenesis. Mutations and deletions in this gene are associated with benign hereditary chorea, choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress, and may be associated with thyroid cancer. Multiple transcript variants encoding different isoforms have been found for this gene. This gene shares the symbol/alias 'TTF1' with another gene, transcription termination factor 1, which plays a role in ribosomal gene transcription. [provided by RefSeq, Feb 2014]

SFTA3 (HGNC:):

NKX2-1-AS1 (HGNC:40585): (NKX2-1 antisense RNA 1)

SFTA3 (HGNC:18387): (surfactant associated 3) Involved in wound healing. Located in cytoplasm and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 14-36519521-T-C is Benign according to our data. Variant chr14-36519521-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 803018.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000144 (22/152332) while in subpopulation AFR AF = 0.000481 (20/41578). AF 95% confidence interval is 0.000319. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 22 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003317.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-1	NM_001079668.3	MANE Select	c.78-151A>G		intron	N/A	NP_001073136.1	P43699-3
	NKX2-1	NM_003317.4		c.-164A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	NP_003308.1	P43699-1
	NKX2-1	NM_003317.4		c.-164A>G		5_prime_UTR	Exon 1 of 2	NP_003308.1	P43699-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-1	ENST00000498187.6	TSL:1	c.-164A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000429607.2	P43699-1
	NKX2-1	ENST00000522719.4	TSL:1	c.-67A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 5	ENSP00000429519.4	P43699-1
	NKX2-1	ENST00000498187.6	TSL:1	c.-164A>G		5_prime_UTR	Exon 1 of 2	ENSP00000429607.2	P43699-1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000159 AC: 22 AN: 1384572 Hom.: 0 Cov.: 31 AF XY: 0.0000102 AC XY: 7 AN XY: 683204

African (AFR) AF: 0.000665 AC: 21 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35744

South Asian (SAS) AF: 0.00 AC: 0 AN: 78390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078732

Other (OTH) AF: 0.0000173 AC: 1 AN: 57892

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74490

African (AFR) AF: 0.000481 AC: 20 AN: 41578

American (AMR) AF: 0.000131 AC: 2 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000178

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Brain-lung-thyroid syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.93
PhyloP100		5.7
PromoterAI		0.015	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1003307358; hg19: chr14-36988726;